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标题翻译：苯并噻吩衍生物及其作为HSTAMINE H3拮抗剂的用途

公开(公告)号：WO2010007382A8

公开(公告)日：2010-03-18

申请号：PCT/GB2009001774

申请日：2009-07-17

申请人： TAKEDA PHARMACEUTICAL , POONI PARMINDER KAUR , MERCHANT KEVIN JOHN , KERR CATRINA , CROSBY STUART RICHARD , OKAWA TOMOHIRO , SASAKI MITSURU , GOTOU MIKA , SHOWELL GRAHAM ANDREW , TEALL MARTIN RICHARD

发明人： POONI PARMINDER KAUR , MERCHANT KEVIN JOHN , KERR CATRINA , CROSBY STUART RICHARD , OKAWA TOMOHIRO , SASAKI MITSURU , GOTOU MIKA , SHOWELL GRAHAM ANDREW , TEALL MARTIN RICHARD

IPC分类号： C07D223/16 , A61K31/55 , A61P25/18 , C07D401/06 , C07D401/12 , C07D401/14 , C07D403/12 , C07D405/12 , C07D405/14 , C07D409/12 , C07D409/14 , C07D413/12 , C07D417/12

CPC分类号： C07D403/12 , C07D223/16 , C07D401/06 , C07D401/12 , C07D401/14 , C07D405/12 , C07D405/14 , C07D409/12 , C07D409/14 , C07D413/12 , C07D417/12

摘要： A compound having the formula (1) wherein: R1 is a group selected from C3-8 cycloalkyl, C1-6 alkyl, C1-6 alkylene-C3-8 cycloalkyl, each of which groups may optionally be substituted with C1-6 alkyl, halogen, haloC1-6 alkyl or OR15, or R1 is heterocyclyl, optionally substituted with C1-6 alkyl, haloC1-6 alkyl or OR15; n is 0, 1, 2, 3 or 4, the alkylene group -(CH2)n- formed thereby being optionally substituted with a group selected from C1-4 alkyl, C3-8 cycloalkyl and arylsulfonyl; A is a group selected from -N(R2)CO-, -CON(R2)-, -OC(O)-, -C(O)O-, -CO-, -C(R2)(OR3)-, -C(=N-O-R3)-, - C(=CR2R3)-, -C3-8 cycloalkylene-, -C(R2)(haloC1-6 alkyl)-, C1-4 alkylene and -C(OR3)(haloC1-6 alkyl)-; R2 and R3 are each independently selected from H, C1-6 alkyl, and C3-8 cycloalkyl, or, when A is -N(R2)CO- and X is absent, R2 may form, together with the adjacent nitrogen atom and Z, an N-containing heterocyclyl group, which may optionally be substituted; X is absent or is C1-4 alkylene or C2-4 alkenylene, each of which may optionally be substituted with one or more C1-4 alkyl groups, OR16, halogen or haloC1-6 alkyl; Z is selected from aryl, heteroaryl, C3-8 cycloalkyl, and heterocyclyl, each of which may optionally be substituted by a group selected from -Y-aryl, -Y-heteroaryl, -Y-C3-8 cycloalkyl and -Y-heterocyclyl, or, when X is present, Z may be H, or, when X is absent and A is -C(R2)(OR3)- or -N(R2)CO-, Z may be H, or, when A is -N(R2)CO- and X is absent, Z may form, together with the adjacent nitrogen atom and R2, an N-containing heterocyclyl group which may optionally be substituted, wherein, when A is -CO-, Z is linked to X or A via a carbon atom and wherein, when A is -N(R2)CO- and Z is H, R1 is C3-8 cycloalkyl; and Y represents a bond, C1-6 alkylene, CO, NR14, COC2-6 alkenylene, O, SO2 or NHCOC1-6 alkylene; wherein said cycloalkyl, aryl, heteroaryl and heterocyclyl groups Z may be optionally substituted by one or more substituents which may be the same or different, and which are selected from halogen, haloC1-6 alkyl, hydroxy, cyano, nitro, =O, -R4, -CO2R4, -COR4, -NR5R6, -C1-6 alkyl-NR5R6, -C3-8 cycloalkyl-NR5R6, - CONR12R13, -NR12COR13, -NR5SO2R6, -OCONR5R6, -NR5CO2R6, -NR4CONR5R6 or -SO2NR5R6- SHR8, -alkyl-OR8, -SOR8, -OR9, -SO2R9, -OSO2R9, -alkyl-SO2R9, -alkyl-CONHR9, -alkyl-SONHR9, -alkyl-COR10, -CO-alkyl-R10, -O-alkyl-R11 (wherein R4, R5 and R6 independently represent hydrogen, C1-6 alkyl, -C3-8 cycloalkyl, -C1-6 alkylene-C3-8 cycloalkyl, aryl, heterocyclyl or heteroaryl, wherein R8 represents C1-6 alkyl, wherein R9 represents C1-6 alkyl or aryl, wherein R10 represents aryl, wherein R11 represents C3-8 cycloalkyl or aryl, R12, R13, R14, R15 and R16 each independently represent H or C1-6 alkyl, and wherein -NR5R6 and -NR12R13 may represent a nitrogen containing heterocyclyl group); wherein said R4, R5, R6 R8, R9, R11 and R11 groups may be optionally substituted by one or more substituents which may be the same or different, and which are selected from the group consisting of halogen, hydroxy, C1-6 alkyl, C1-6 alkoxy, cyano, amino, =O or trifluoromethyl; and wherein substituents of Z selected from -Y-aryl, -Y-heteroaryl, -Y-C3-8cycloalkyl and -Y-heterocyclyl may be optionally substituted by one or more substituents selected from =O, hydroxy, cyano, nitro, halogen, haloC1-6 alkyl and C1-6alkyl; and wherein, when A is C1-4 alkylene, said cycloalkyl, aryl, heteroaryl or heterocyclyl group Z (such as a heterocyclyl group Z) is substituted at least with hydroxy, CF3, or =0; and wherein, when A is CON(R2) n is 1; or a pharmaceutically acceptable salt or ester thereof, provided that: when A is -CO-, R1 is CH3, C3-8 cycloalkyl-substituted C1-6 alkylene or n-butyl, n is 0 and X is -CH2CH2-, Z is not N-benzyl substituted 4-piperidinyl, N-(3-fluorobenzyl)-substituted 4-piperidinyl or N-acetyl substituted 4-piperidinyl; when A is -OC(O)-, R1 is cyclobutyl, n is 0 and X is -CH2CH2-, Z is not H; when A is -OC(O)-, R1 is n-propyl, n is 0 and X is -CH2-, Z is not H; and when A is -CO-, R1 is CH3, n is 0 and X is CH2, Z is not H.

摘要翻译：具有式（1）的化合物，其中：R 1是选自C 3-8环烷基，C 1-6烷基，C 1-6亚烷基-C 3-8环烷基，其各自可以任选被C 1-6烷基取代，卤素，卤代C 1-6烷基或OR 15，或R 1是任选被C 1-6烷基，卤代C 1-6烷基或OR 15取代的杂环基; n为0,1,2,3或4，由此形成的亚烷基 - （CH 2）n任选被选自C 1-4烷基，C 3-8环烷基和芳基磺酰基的基团取代; A是选自-N（R2）CO-，-CON（R2） - ，-OC（O） - ， - （O）O-，-CO-，-C（R2）（OR3） -C（= NO-R 3） - ， - C（= CR 2 R 3） - ， - C 3-8亚环烷基 - ， - C（R 2）（卤代C 1-6烷基） - ，C 1-4亚烷基和-C（OR 3） -6烷基） - ; R2和R3各自独立地选自H，C1-6烷基和C3-8环烷基，或当A是-N（R2）CO-且X不存在时，R2可以与相邻的氮原子和Z ，可以任选被取代的含N的杂环基; X不存在或是C 1-4亚烷基或C 2-4亚烯基，其各自可以任选被一个或多个C 1-4烷基，OR 16，卤素或卤代C 1-6烷基取代; Z选自芳基，杂芳基，C 3-8环烷基和杂环基，其各自可任选被选自-Y-芳基，-Y-杂芳基，-Y-C 3-8环烷基和-Y-杂环基或当X存在时，Z可以是H，或者当X不存在且A是-C（R 2）（OR 3） - 或-N（R 2）CO-时，Z可以是H，或者当A是 -N（R2）CO-和X不存在，Z可以与相邻的氮原子一起形成，R 2可以任选被取代的含N的杂环基，其中当A是-CO-时，Z连接到 X或A通过碳原子，并且其中当A是-N（R 2）CO-且Z是H时，R 1是C 3-8环烷基; Y表示键，C 1-6亚烷基，CO，NR 14，COC 2-6亚烯基，O，SO 2或NHCOC 1-6亚烷基; 其中所述环烷基，芳基，杂芳基和杂环基基团Z可以任选地被一个或多个可以相同或不同的取代基取代，并且选自卤素，卤代C 1-6烷基，羟基，氰基，硝基，= O - R4，-CO 2 R 4，-COR 4，-NR 5 R 6，-C 1-6烷基-NR 5 R 6，-C 3-8环烷基-NR 5 R 6，-CONR 12 R 13，-NR 12 COR 13，-NR 5 SO 2 R 6，-OCONR 5 R 6，-NR 5 CO 2 R 6，-NR 4 CONR 5 R 6或-SO 2 NR 5 R 6 -SHR 8， - 烷基-OR 8，-SOR 8，-OR 9，-SO 2 R 9，-OSO 2 R 9， - 烷基-SO 2 R 9 - - 烷基-CONHR 9 - - 烷基-SHHR 9， - 烷基-CON10，-CO-烷基-R10，-O-烷基-R11 （其中R 4，R 5和R 6独立地表示氢，C 1-6烷基，-C 3-8环烷基，-C 1-6亚烷基-C 3-8环烷基，芳基，杂环基或杂芳基，其中R 8表示C 1-6烷基， C 1-6烷基或芳基，其中R 10表示芳基，其中R 11表示C 3-8环烷基或芳基，R 12，R 13，R 14，R 15和R 16各自独立地表示H或C 1-6烷基，并且其中-NR 5 R 6和-NR 12 R 13可以表示含氮杂环基）; 其中所述R 4，R 5，R 6，R 8，R 9，R 11和R 11基团可以任选地被一个或多个可以相同或不同的取代基取代，并且选自卤素，羟基，C 1-6烷基， C 1-6烷氧基，氰基，氨基，= O或三氟甲基; 并且其中选自-Y-芳基，-Y-杂芳基，-Y-C3-8环烷基和-Y-杂环基的Z的取代基可以任选地被一个或多个选自以下的取代基取代：选自= O，羟基，氰基，硝基，卤素，卤代C 1-6烷基和C 1-6烷基; 并且其中当A为C 1-4亚烷基时，所述环烷基，芳基，杂芳基或杂环基Z（例如杂环基Z）至少被羟基，CF 3或= 0取代; 并且其中当A是CON（R2）时，n是1; 或其药学上可接受的盐或酯，条件是：当A为-CO-时，R 1为CH 3，C 3-8环烷基取代的C 1-6亚烷基或正丁基，n为0且X为-CH 2 CH 2 - ，Z为不是N-苄基取代的4-哌啶基，N-（3-氟苄基）取代的4-哌啶基或N-乙酰基取代的4-哌啶基; 当A为-OC（O） - 时，R1为环丁基，n为0，X为-CH2CH2-，Z为H; 当A为-OC（O） - 时，R 1为正丙基，n为0且X为-CH 2 - ，Z不为H; 当A为-CO-时，R 1为CH 3，n为0，X为CH 2，Z为H。

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